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Autoinflammation and autoimmunity across rheumatic and musculoskeletal diseases

Nature Reviews Rheumatology volume 17, pages 585–595 (2021)Cite this article

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Abstract

Most rheumatic and musculoskeletal diseases (RMDs) can be placed along a spectrum of disorders, with autoinflammatory diseases (including monogenic systemic autoinflammatory diseases) and autoimmune diseases (such as systemic lupus erythematosus and antiphospholipid syndrome) representing the two ends of this spectrum. However, although most autoinflammatory diseases are characterized by the activation of innate immunity and inflammasomes and classical autoimmunity typically involves adaptive immune responses, there is some overlap in the features of autoimmunity and autoinflammation in RMDs. Indeed, some ‘mixed-pattern’ diseases such as spondyloarthritis and some forms of rheumatoid arthritis can also be delineated. A better understanding of the pathogenic pathways of autoinflammation and autoimmunity in RMDs, as well as the preferential cytokine patterns observed in these diseases, could help us to design targeted treatment strategies.

Key points

  • Rheumatic and musculoskeletal diseases (RMDs) form a continuum between classical autoimmune and autoinflammatory conditions.

  • Classical autoinflammatory and autoimmune diseases are associated with the activation of innate immunity and adaptive immune responses, respectively.

  • There are some ‘mixed-pattern’ disorders that carry the features of both autoimmune and autoinflammatory conditions, and one disorder might have autoimmune and autoinflammatory characteristics at different stages of disease development.

  • The autoimmune, autoinflammatory or mixed phenotype of RMDs might help us to develop and administer therapies targeted to specific disease phenotypes.

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Fig. 1: Spectrum of autoinflammatory, mixed-pattern and autoimmune diseases.
Fig. 2: Cellular mediators of autoimmunity and autoinflammation.

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References

  1. Hedrich, C. M. & Tsokos, G. C. Bridging the gap between autoinflammation and autoimmunity. Clin. Immunol. 147, 151–154 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Abbas, A., Lichtman A. H., Pillai S. Cellular and Molecular Immunology 9th edn (Elsevier, 2017).

  3. Hedrich, C. M. Shaping the spectrum — from autoinflammation to autoimmunity. Clin. Immunol. 165, 21–28 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. McGonagle, D. & McDermott, M. F. A proposed classification of the immunological diseases. PLoS Med. 3, e297 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Davidson, A. & Diamond, B. Autoimmune diseases. N. Engl. J. Med. 345, 340–350 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Masters, S. L. Broadening the definition of autoinflammation. Semin. Immunopathol. 37, 311–312 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Michels, A. W. & Gottlieb, P. A. Autoimmune polyglandular syndromes. Nat. Rev. Endocrinol. 6, 270–277 (2010).

    Article  CAS  PubMed  Google Scholar 

  8. McGonagle, D., Watad, A. & Savic, S. Mechanistic immunological based classification of rheumatoid arthritis. Autoimmun. Rev. 17, 1115–1123 (2018).

    Article  CAS  PubMed  Google Scholar 

  9. Savic, S. et al. Autoimmune-autoinflammatory rheumatoid arthritis overlaps: a rare but potentially important subgroup of diseases. RMD Open 3, e000550 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Smolen, J. S. et al. Rheumatoid arthritis. Nat. Rev. Dis. Prim. 4, 18001 (2018).

    Article  PubMed  Google Scholar 

  11. Kuek, A., Hazleman, B. L. & Ostor, A. J. Immune-mediated inflammatory diseases (IMIDs) and biologic therapy: a medical revolution. Postgrad. Med. J. 83, 251–260 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Szekanecz, Z., Szamosi, S., Kovacs, G. E., Kocsis, E. & Benko, S. The NLRP3 inflammasome–interleukin 1 pathway as a therapeutic target in gout. Arch. Biochem. Biophys. 670, 82–93 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Frizinsky, S. et al. The innate immune perspective of autoimmune and autoinflammatory conditions. Rheumatology 58, vi1–vi8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Melki, I. & Fremond, M. L. Type I Interferonopathies: from a novel concept to targeted therapeutics. Curr. Rheumatol. Rep. 22, 32 (2020).

    Article  PubMed  Google Scholar 

  15. Tsokos, G. C. Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110–2121 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Cook, H. T. & Botto, M. Mechanisms of disease: the complement system and the pathogenesis of systemic lupus erythematosus. Nat. Clin. Pract. Rheumatol. 2, 330–337 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. David, T., Ling, S. F. & Barton, A. Genetics of immune-mediated inflammatory diseases. Clin. Exp. Immunol. 193, 3–12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Crow, M. K. Advances in understanding the role of type I interferons in systemic lupus erythematosus. Curr. Opin. Rheumatol. 26, 467–474 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Crispin, J. C., Hedrich, C. M. & Tsokos, G. C. Gene-function studies in systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 476–484 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Brown, E. E., Edberg, J. C. & Kimberly, R. P. Fc receptor genes and the systemic lupus erythematosus diathesis. Autoimmunity 40, 567–581 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Trinchieri, G. Type I interferon: friend or foe? J. Exp. Med. 207, 2053–2063 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Brkic, Z. et al. The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis. Ann. Rheum. Dis. 75, 1567–1573 (2016).

    Article  CAS  PubMed  Google Scholar 

  23. Wu, M. & Assassi, S. The role of type 1 interferon in systemic sclerosis. Front. Immunol. 4, 266 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Greenberg, S. A. et al. Relationship between disease activity and type 1 interferon- and other cytokine-inducible gene expression in blood in dermatomyositis and polymyositis. Genes. Immun. 13, 207–213 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Wong, D. et al. Interferon and biologic signatures in dermatomyositis skin: specificity and heterogeneity across diseases. PLoS ONE 7, e29161 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chiche, L. & Cornec, D. Mysterious uncoupled clinical symptoms and interferon signature in Sjogren’s syndrome: limitations of current approaches for unravelling complexity? Rheumatology 59, 5–6 (2019).

    Article  Google Scholar 

  27. Brkic, Z. et al. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjogren’s syndrome and association with disease activity and BAFF gene expression. Ann. Rheum. Dis. 72, 728–735 (2013).

    Article  CAS  PubMed  Google Scholar 

  28. Klareskog, L., Malmstrom, V., Lundberg, K., Padyukov, L. & Alfredsson, L. Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Semin. Immunol. 23, 92–98 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Gordon, R. A., Grigoriev, G., Lee, A., Kalliolias, G. D. & Ivashkiv, L. B. The interferon signature and STAT1 expression in rheumatoid arthritis synovial fluid macrophages are induced by tumor necrosis factor α and counter-regulated by the synovial fluid microenvironment. Arthritis Rheum. 64, 3119–3128 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. McInnes, I. B. & O’Dell, J. R. State-of-the-art: rheumatoid arthritis. Ann. Rheum. Dis. 69, 1898–1906 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Kahlenberg, J. M. & Kang, I. Advances in disease mechanisms and translational technologies: clinicopathologic significance of inflammasome activation in autoimmune diseases. Arthritis Rheumatol. 72, 386–395 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kraetsch, H. G., Antoni, C., Kalden, J. R. & Manger, B. Successful treatment of a small cohort of patients with adult onset of Still’s disease with infliximab: first experiences. Ann. Rheum. Dis. 60 (Suppl. 3), iii55–iii57 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Betrains, A. et al. Systemic autoinflammatory disease in adults. Autoimmun. Rev. 20, 102774 (2021).

    Article  CAS  PubMed  Google Scholar 

  34. Krainer, J., Siebenhandl, S. & Weinhausel, A. Systemic autoinflammatory diseases. J. Autoimmun. 109, 102421 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nirmala, N. et al. Gene-expression analysis of adult-onset Still’s disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity. Pediatr. Rheumatol. Online J. 13, 50 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Rowczenio, D. M. et al. Molecular genetic investigation, clinical features, and response to treatment in 21 patients with Schnitzler syndrome. Blood 131, 974–981 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Georgin-Lavialle, S. et al. Systemic autoinflammatory diseases: clinical state of the art. Best Pract. Res. Clin. Rheumatol. 34, 101529 (2020).

    Article  PubMed  Google Scholar 

  38. Ter Haar, N. M. et al. Development of the autoinflammatory disease damage index (ADDI). Ann. Rheum. Dis. 76, 821–830 (2017).

    Article  PubMed  Google Scholar 

  39. ter Haar, N. M. et al. Recommendations for the management of autoinflammatory diseases. Ann. Rheum. Dis. 74, 1636–1644 (2015).

    Article  PubMed  CAS  Google Scholar 

  40. Martinon, F. & Aksentijevich, I. New players driving inflammation in monogenic autoinflammatory diseases. Nat. Rev. Rheumatol. 11, 11–20 (2015).

    Article  CAS  PubMed  Google Scholar 

  41. Holzinger, D., Kessel, C., Omenetti, A. & Gattorno, M. From bench to bedside and back again: translational research in autoinflammation. Nat. Rev. Rheumatol. 11, 573–585 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Savic, S., Caseley, E. A. & McDermott, M. F. Moving towards a systems-based classification of innate immune-mediated diseases. Nat. Rev. Rheumatol. 16, 222–237 (2020).

    Article  PubMed  Google Scholar 

  43. Dinarello, C. A. The IL-1 family of cytokines and receptors in rheumatic diseases. Nat. Rev. Rheumatol. 15, 612–632 (2019).

    Article  CAS  PubMed  Google Scholar 

  44. Swanson, K. V., Deng, M. & Ting, J. P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol. 19, 477–489 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cudrici, C., Deuitch, N. & Aksentijevich, I. Revisiting TNF receptor-associated periodic syndrome (TRAPS): current perspectives. Int. J. Mol. Sci. 21, 3263 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  46. McDermott, M. F. et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97, 133–144 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Bruck, N., Schnabel, A. & Hedrich, C. M. Current understanding of the pathophysiology of systemic juvenile idiopathic arthritis (sJIA) and target-directed therapeutic approaches. Clin. Immunol. 159, 72–83 (2015).

    Article  CAS  PubMed  Google Scholar 

  48. Kessel, C., Hedrich, C. M. & Foell, D. Innately adaptive or truly autoimmune: is there something unique about systemic juvenile idiopathic arthritis? Arthritis Rheumatol. 72, 210–219 (2020).

    Article  PubMed  Google Scholar 

  49. Ter Haar, N. M., Jansen, M. H. A., Frenkel, J. F. & Vastert, S. J. How autoinflammation may turn into autoimmune inflammation: insights from monogenetic and complex IL-1 mediated auto-inflammatory diseases. Clin. Immunol. 219, 108538 (2020).

    Article  PubMed  CAS  Google Scholar 

  50. Nigrovic, P. A. Review: is there a window of opportunity for treatment of systemic juvenile idiopathic arthritis? Arthritis Rheumatol. 66, 1405–1413 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Rock, K. L., Kataoka, H. & Lai, J. J. Uric acid as a danger signal in gout and its comorbidities. Nat. Rev. Rheumatol. 9, 13–23 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Martinon, F., Petrilli, V., Mayor, A., Tardivel, A. & Tschopp, J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440, 237–241 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Gerfaud-Valentin, M., Jamilloux, Y., Iwaz, J. & Seve, P. Adult-onset Still’s disease. Autoimmun. Rev. 13, 708–722 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Sighart, R. et al. Evidence for genetic overlap between adult onset Still’s disease and hereditary periodic fever syndromes. Rheumatol. Int. 38, 111–120 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Marshall, S. E. Behcet’s disease. Best Pract. Res. Clin. Rheumatol. 18, 291–311 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. McGonagle, D., Aydin, S. Z., Gul, A., Mahr, A. & Direskeneli, H. ‘MHC-I-opathy’-unified concept for spondyloarthritis and Behcet disease. Nat. Rev. Rheumatol. 11, 731–740 (2015).

    Article  CAS  PubMed  Google Scholar 

  57. Gul, A. Behcet’s disease as an autoinflammatory disorder. Curr. Drug Targets Inflamm. Allergy 4, 81–83 (2005).

    Article  PubMed  Google Scholar 

  58. Bonnekoh, H. et al. Skin and systemic inflammation in Schnitzler’s syndrome are associated with neutrophil extracellular trap formation. Front. Immunol. 10, 546 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Simon, A. et al. Schnitzler’s syndrome: diagnosis, treatment, and follow-up. Allergy 68, 562–568 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Pathak, S. et al. Exploratory study of MYD88 L265P, rare NLRP3 variants, and clonal hematopoiesis prevalence in patients with Schnitzler syndrome. Arthritis Rheumatol. 71, 2121–2125 (2019).

    Article  CAS  PubMed  Google Scholar 

  61. Generali, E., Bose, T., Selmi, C., Voncken, J. W. & Damoiseaux, J. Nature versus nurture in the spectrum of rheumatic diseases: classification of spondyloarthritis as autoimmune or autoinflammatory. Autoimmun. Rev. 17, 935–941 (2018).

    Article  CAS  PubMed  Google Scholar 

  62. Deodhar, A., Miossec, P. & Baraliakos, X. Is undifferentiated spondyloarthritis a discrete entity? A debate. Autoimmun. Rev. 17, 29–32 (2018).

    Article  PubMed  Google Scholar 

  63. Chimenti, M. S. et al. Auto-reactions, autoimmunity and psoriatic arthritis. Autoimmun. Rev. 14, 1142–1146 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Bodnar, N. et al. Anti-mutated citrullinated vimentin (anti-MCV) and anti-65 kDa heat shock protein (anti-hsp65): new biomarkers in ankylosing spondylitis. Jt. Bone Spine 79, 63–66 (2012).

    Article  CAS  Google Scholar 

  65. Liu, Y., Liao, X. & Shi, G. Autoantibodies in spondyloarthritis, focusing on anti-CD74 antibodies. Front. Immunol. 10, 5 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Schett, G., Elewaut, D., McInnes, I. B., Dayer, J. M. & Neurath, M. F. How cytokine networks fuel inflammation: toward a cytokine-based disease taxonomy. Nat. Med. 19, 822–824 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Pazar, B. et al. Association of ARTS1 gene polymorphisms with ankylosing spondylitis in the Hungarian population: the rs27044 variant is associated with HLA-B*2705 subtype in Hungarian patients with ankylosing spondylitis. J. Rheumatol. 37, 379–384 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Alippe, Y. & Mbalaviele, G. Omnipresence of inflammasome activities in inflammatory bone diseases. Semin. Immunopathol. 41, 607–618 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Szekanecz, Z. & Koch, A. E. Macrophages and their products in rheumatoid arthritis. Curr. Opin. Rheumatol. 19, 289–295 (2007).

    Article  PubMed  Google Scholar 

  70. Yang, C. A., Huang, S. T. & Chiang, B. L. Association of NLRP3 and CARD8 genetic polymorphisms with juvenile idiopathic arthritis in a Taiwanese population. Scand. J. Rheumatol. 43, 146–152 (2014).

    Article  PubMed  Google Scholar 

  71. Maria, A. T. et al. Adult onset Still’s disease (AOSD) in the era of biologic therapies: dichotomous view for cytokine and clinical expressions. Autoimmun. Rev. 13, 1149–1159 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Zhou, Q. et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat. Genet. 48, 67–73 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Guo, C. et al. NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. Clin. Exp. Immunol. 194, 231–243 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mathews, R. J. et al. Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment. Ann. Rheum. Dis. 73, 1202–1210 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Dong, X. et al. ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammasome. Cell Mol. Immunol. 17, 261–271 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Kahlenberg, J. M. & Kaplan, M. J. The inflammasome and lupus: another innate immune mechanism contributing to disease pathogenesis? Curr. Opin. Rheumatol. 26, 475–481 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kim, S. K., Cho, Y. J. & Choe, J. Y. NLRP3 inflammasomes and NLRP3 inflammasome-derived proinflammatory cytokines in peripheral blood mononuclear cells of patients with ankylosing spondylitis. Clin. Chim. Acta 486, 269–274 (2018).

    Article  CAS  PubMed  Google Scholar 

  78. Kastbom, A. et al. Genetic variants in CARD8 but not in NLRP3 are associated with ankylosing spondylitis. Scand. J. Rheumatol. 42, 465–468 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Strand, V. & Kavanaugh, A. F. The role of interleukin-1 in bone resorption in rheumatoid arthritis. Rheumatology 43 (Suppl. 3), iii10–iii16 (2004).

    PubMed  Google Scholar 

  80. Watt, I. & Cobby, M. Treatment of rheumatoid arthritis patients with interleukin-1 receptor antagonist: radiologic assessment. Semin. Arthritis Rheum. 30, 21–25 (2001).

    Article  CAS  PubMed  Google Scholar 

  81. Guo, C. et al. Pathogenesis of lupus nephritis: RIP3 dependent necroptosis and NLRP3 inflammasome activation. J. Autoimmun. 103, 102286 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Deuteraiou, K., Kitas, G., Garyfallos, A. & Dimitroulas, T. Novel insights into the role of inflammasomes in autoimmune and metabolic rheumatic diseases. Rheumatol. Int. 38, 1345–1354 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Henderson, J. & O’Reilly, S. Inflammasome lights up in systemic sclerosis. Arthritis Res. Ther. 19, 205 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Martinez-Godinez, M. A. et al. Expression of NLRP3 inflammasome, cytokines and vascular mediators in the skin of systemic sclerosis patients. Isr. Med. Assoc. J. 17, 5–10 (2015).

    PubMed  Google Scholar 

  85. Vakrakou, A. G. et al. Systemic activation of NLRP3 inflammasome in patients with severe primary Sjogren’s syndrome fueled by inflammagenic DNA accumulations. J. Autoimmun. 91, 23–33 (2018).

    Article  CAS  PubMed  Google Scholar 

  86. Yin, X., Han, G. C., Jiang, X. W., Shi, Q. & Pu, C. Q. Increased expression of the NOD-like receptor family, pyrin domain containing 3 inflammasome in dermatomyositis and polymyositis is a potential contributor to their pathogenesis. Chin. Med. J. 129, 1047–1052 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Barrat, F. J., Crow, M. K. & Ivashkiv, L. B. Interferon target-gene expression and epigenomic signatures in health and disease. Nat. Immunol. 20, 1574–1583 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Goel, R. R. & Kaplan, M. J. Deadliest catch: neutrophil extracellular traps in autoimmunity. Curr. Opin. Rheumatol. 32, 64–70 (2020).

    Article  CAS  PubMed  Google Scholar 

  90. Mutua, V. & Gershwin, L. J. A review of neutrophil extracellular traps (NETs) in disease: potential anti-NETs therapeutics. Clin. Rev. Allergy Immunol. https://doi.org/10.1007/s12016-020-08804-7 (2020).

    Article  PubMed Central  Google Scholar 

  91. Schett, G., Schauer, C., Hoffmann, M. & Herrmann, M. Why does the gout attack stop? A roadmap for the immune pathogenesis of gout. RMD Open 1, e000046 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Delgado-Rizo, V. et al. Neutrophil extracellular traps and its implications in inflammation: an overview. Front. Immunol. 8, 81 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Villanueva, E. et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187, 538–552 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Gul, A. Dynamics of inflammatory response in autoinflammatory disorders: autonomous and hyperinflammatory states. Front. Immunol. 9, 2422 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Ikeda, S. et al. Excess IL-1 signaling enhances the development of TH17 cells by downregulating TGF-β-induced Foxp3 expression. J. Immunol. 192, 1449–1458 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Dougados, M. et al. Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann. Rheum. Dis. 73, 62–68 (2014).

    Article  PubMed  Google Scholar 

  98. Radner, H., Yoshida, K., Smolen, J. S. & Solomon, D. H. Multimorbidity and rheumatic conditions — enhancing the concept of comorbidity. Nat. Rev. Rheumatol. 10, 252–256 (2014).

    Article  PubMed  Google Scholar 

  99. Szekanecz, Z. et al. Autoimmune atherosclerosis in 3D: how it develops, how to diagnose and what to do. Autoimmun. Rev. 15, 756–769 (2016).

    Article  CAS  PubMed  Google Scholar 

  100. Szekanecz, Z., Kerekes, G., Kardos, Z., Baráth, Z. & Tamási, L. Mechanisms of inflammatory atherosclerosis in rheumatoid arthritis. Curr. Immunol. Rev. 12, 35–46 (2016).

    Article  CAS  Google Scholar 

  101. Agca, R. et al. EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 update. Ann. Rheum. Dis. 76, 17–28 (2017).

    Article  CAS  PubMed  Google Scholar 

  102. Geraldino-Pardilla, L. et al. Association of anti-citrullinated peptide antibodies with coronary artery calcification in rheumatoid arthritis. Arthritis Care Res. 69, 1276–1281 (2017).

    Article  CAS  Google Scholar 

  103. Sokolove, J. et al. Brief report: citrullination within the atherosclerotic plaque: a potential target for the anti-citrullinated protein antibody response in rheumatoid arthritis. Arthritis Rheum. 65, 1719–1724 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Spinelli, F. R. et al. Association between antibodies to carbamylated proteins and subclinical atherosclerosis in rheumatoid arthritis patients. BMC Musculoskelet. Disord. 18, 214 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Lopez-Mejias, R. et al. Influence of elevated-CRP level-related polymorphisms in non-rheumatic Caucasians on the risk of subclinical atherosclerosis and cardiovascular disease in rheumatoid arthritis. Sci. Rep. 6, 31979 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kastbom, A., Arlestig, L. & Rantapaa-Dahlqvist, S. Genetic variants of the NLRP3 inflammasome are associated with stroke in patients with rheumatoid arthritis. J. Rheumatol. 42, 1740–1745 (2015).

    Article  CAS  PubMed  Google Scholar 

  107. Paramel Varghese, G. et al. NLRP3 inflammasome expression and activation in human atherosclerosis. J. Am. Heart Assoc. 5, e003031 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Ahmed, A. et al. Brief report: proatherogenic cytokine microenvironment in the aortic adventitia of patients with rheumatoid arthritis. Arthritis Rheumatol. 68, 1361–1366 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Blankenberg, S. et al. Interleukin-18 is a strong predictor of cardiovascular death in stable and unstable angina. Circulation 106, 24–30 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Cacoub, P. & Marques, C. Acute recurrent pericarditis: from pathophysiology towards new treatment strategy. Heart 106, 1046–1051 (2020).

    Article  CAS  PubMed  Google Scholar 

  111. Kontzias, A., Barkhodari, A. & Yao, Q. Pericarditis in systemic rheumatologic diseases. Curr. Cardiol. Rep. 22, 142 (2020).

    Article  PubMed  Google Scholar 

  112. Cantarini, L. et al. Autoimmunity and autoinflammation as the yin and yang of idiopathic recurrent acute pericarditis. Autoimmun. Rev. 14, 90–97 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Mecoli, C. A. & Christopher-Stine, L. Management of interstitial lung disease in patients with myositis specific autoantibodies. Curr. Rheumatol. Rep. 20, 27 (2018).

    Article  PubMed  CAS  Google Scholar 

  114. Castillo-Tandazo, W., Gonzalez, J. & Flores-Fortty, A. Pathogenesis and therapeutics of interstitial lung disease in systemic sclerosis. Curr. Rheumatol. Rev. 9, 105–112 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Lasithiotaki, I. et al. NLRP3 inflammasome expression in idiopathic pulmonary fibrosis and rheumatoid lung. Eur. Respir. J. 47, 910–918 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Duarte-Delgado, N. P., Vasquez, G. & Ortiz-Reyes, B. L. Blood–brain barrier disruption and neuroinflammation as pathophysiological mechanisms of the diffuse manifestations of neuropsychiatric systemic lupus erythematosus. Autoimmun. Rev. 18, 426–432 (2019).

    Article  CAS  PubMed  Google Scholar 

  117. Masson, C. et al. Adult Still’s disease: part I. Manifestations and complications in sixty-five cases in France. Rev. Rhum. Engl. Ed. 62, 748–757 (1995).

    CAS  PubMed  Google Scholar 

  118. Szentpetery, A. et al. Effects of targeted therapies on the bone in arthritides. Autoimmun. Rev. 16, 313–320 (2017).

    Article  CAS  PubMed  Google Scholar 

  119. Dinarello, C. A. & van der Meer, J. W. Treating inflammation by blocking interleukin-1 in humans. Semin. Immunol. 25, 469–484 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Cantarini, L. et al. Interleukin-1: Ariadne’s thread in autoinflammatory and autoimmune disorders. Isr. Med. Assoc. J. 17, 93–97 (2015).

    PubMed  Google Scholar 

  121. Schett, G., Dayer, J. M. & Manger, B. Interleukin-1 function and role in rheumatic disease. Nat. Rev. Rheumatol. 12, 14–24 (2016).

    Article  CAS  PubMed  Google Scholar 

  122. European Commission. Ilaris alkalmazási előírás. https://ec.europa.eu/health/documents/community-register/2016/20160801135455/anx_135455_hu.pdf (2016).

  123. Kuemmerle-Deschner, J. B. et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res. Ther. 13, R34 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Hoffman, H. M. et al. Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extension study. Clin. Ther. 34, 2091–2103 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Hoffman, H. M. et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 58, 2443–2452 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Kuemmerle-Deschner, J. B. et al. Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle–Wells syndrome. Arthritis Rheum. 63, 840–849 (2011).

    Article  PubMed  Google Scholar 

  127. Schlesinger, N. Canakinumab in gout. Expert Opin. Biol. Ther. 12, 1265–1275 (2012).

    Article  CAS  PubMed  Google Scholar 

  128. Terkeltaub, R. et al. The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study. Ann. Rheum. Dis. 68, 1613–1617 (2009).

    Article  CAS  PubMed  Google Scholar 

  129. So, A., De Smedt, T., Revaz, S. & Tschopp, J. A pilot study of IL-1 inhibition by anakinra in acute gout. Arthritis Res. Ther. 9, R28 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Vitale, A., Cantarini, L., Rigante, D., Bardelli, M. & Galeazzi, M. Anakinra treatment in patients with gout and type 2 diabetes. Clin. Rheumatol. 34, 981–984 (2015).

    Article  PubMed  Google Scholar 

  131. Ruperto, N. et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2396–2406 (2012).

    Article  CAS  PubMed  Google Scholar 

  132. Ruperto, N. et al. A phase II, multicenter, open-label study evaluating dosing and preliminary safety and efficacy of canakinumab in systemic juvenile idiopathic arthritis with active systemic features. Arthritis Rheum. 64, 557–567 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Yokota, S. et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 371, 998–1006 (2008).

    Article  CAS  PubMed  Google Scholar 

  134. Quartier, P. et al. A multicentre, randomised, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann. Rheum. Dis. 70, 747–754 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Ilowite, N. T. et al. Randomized, double-blind, placebo-controlled trial of the efficacy and safety of rilonacept in the treatment of systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 66, 2570–2579 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Kedor, C. et al. Canakinumab for Treatment of Adult-Onset Still’s Disease to Achieve Reduction of Arthritic Manifestation (CONSIDER): phase II, randomised, double-blind, placebo-controlled, multicentre, investigator-initiated trial. Ann. Rheum. Dis. 79, 1090–1097 (2020).

    Article  CAS  PubMed  Google Scholar 

  137. Junge, G., Mason, J. & Feist, E. Adult onset Still’s disease — the evidence that anti-interleukin-1 treatment is effective and well-tolerated (a comprehensive literature review). Semin. Arthritis Rheum. 47, 295–302 (2017).

    Article  CAS  PubMed  Google Scholar 

  138. Castaneda, S. et al. Tocilizumab for the treatment of adult-onset Still’s disease. Expert. Opin. Biol. Ther. 19, 273–286 (2019).

    Article  CAS  PubMed  Google Scholar 

  139. Vitale, A. et al. Interleukin-1 inhibition in Behcet’s disease. Isr. Med. Assoc. J. 18, 171–176 (2016).

    PubMed  Google Scholar 

  140. de Koning, H. D. et al. Sustained efficacy of the monoclonal anti-interleukin-1β antibody canakinumab in a 9-month trial in Schnitzler’s syndrome. Ann. Rheum. Dis. 72, 1634–1638 (2013).

    Article  PubMed  CAS  Google Scholar 

  141. Garcia-Carrasco, M. et al. Use of rituximab in patients with systemic lupus erythematosus: an update. Autoimmun. Rev. 8, 343–348 (2009).

    Article  CAS  PubMed  Google Scholar 

  142. McQueen, F. M. & Solanki, K. Rituximab in diffuse cutaneous systemic sclerosis: should we be using it today? Rheumatology 54, 757–767 (2015).

    Article  CAS  PubMed  Google Scholar 

  143. Rios Fernandez, R., Callejas Rubio, J. L., Sanchez Cano, D., Saez Moreno, J. A. & Ortego Centeno, N. Rituximab in the treatment of dermatomyositis and other inflammatory myopathies. A report of 4 cases and review of the literature. Clin. Exp. Rheumatol. 27, 1009–1016 (2009).

    CAS  PubMed  Google Scholar 

  144. Grigoriadou, S. et al. B cell depletion with rituximab in the treatment of primary Sjogren’s syndrome: what have we learnt? Clin. Exp. Rheumatol. 37 (Suppl 118), 217–224 (2019).

    PubMed  Google Scholar 

  145. Navarra, S. V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377, 721–731 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Pimentel-Quiroz, V. R., Ugarte-Gil, M. F. & Alarcon, G. S. Abatacept for the treatment of systemic lupus erythematosus. Expert Opin. Invest. Drugs 25, 493–499 (2016).

    Article  CAS  Google Scholar 

  147. Boleto, G., Allanore, Y. & Avouac, J. Targeting costimulatory pathways in systemic sclerosis. Front. Immunol. 9, 2998 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Machado, A. C. et al. Effectiveness and safety of abatacept for the treatment of patients with primary Sjogren’s syndrome. Clin. Rheumatol. 39, 243–248 (2019).

    Article  PubMed  Google Scholar 

  149. Khanna, D. et al. Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate). Ann. Rheum. Dis. 77, 212–220 (2018).

    Article  CAS  PubMed  Google Scholar 

  150. Alten, R. & Maleitzke, T. Tocilizumab: a novel humanized anti-interleukin 6 (IL-6) receptor antibody for the treatment of patients with non-RA systemic, inflammatory rheumatic diseases. Ann. Med. 45, 357–363 (2013).

    Article  CAS  PubMed  Google Scholar 

  151. Illei, G. G. et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 62, 542–552 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Jamilloux, Y. et al. JAK inhibitors for the treatment of autoimmune and inflammatory diseases. Autoimmun. Rev. 18, 102390 (2019).

    Article  CAS  PubMed  Google Scholar 

  153. Chauhan, D., Vande Walle, L. & Lamkanfi, M. Therapeutic modulation of inflammasome pathways. Immunol. Rev. 297, 123–138 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the European Union Social Fund TAMOP-4.2.4.A/2-11/1-2012-0001 ‘National Excellence Program’ and the European Union GINOP-2.3.2-15-2016-00015 and GINOP-2.3.2-15-2016-00050 grants (to Z.S.). It was also supported by the Hungarian National Scientific Research Fund (NKFIH-OTKA Grant No. K131844 to S.B.) and the Faculty of Medicine of the University of Debrecen (1G3DBKD0TUDF 247 to S.B.).

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Authors and Affiliations

  1. Division of Rheumatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Zoltán Szekanecz, Szilvia Szamosi & Gabriella Szűcs

  2. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK

    Iain B. McInnes

  3. Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Georg Schett

  4. Deutsches Zentrum fur Immuntherapie, Friedrich Alexander University Erlangen-Nuremberg and Universitätsklinikum Erlangen, Erlangen, Germany

    Georg Schett

  5. Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Szilvia Benkő

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Szekanecz, Z., McInnes, I.B., Schett, G. et al. Autoinflammation and autoimmunity across rheumatic and musculoskeletal diseases. Nat Rev Rheumatol 17, 585–595 (2021). https://doi.org/10.1038/s41584-021-00652-9

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